Impairment of ischemia-induced vascular functions by PS1 FAD mutants

PS1 FAD 突变体对缺血诱导的血管功能的损害

• 批准号: 10328960
• 负责人: Anastasios Georgakopoulos
• 金额: $ 60.51万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-15 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10328960
• 关键词: Adult; Affect; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; Angiogenic Factor; Angiogenic Peptides; Angiogenic Proteins; Area; Atrophic; Attenuated; Blood; Blood Vessels; Blood capillaries; Blood flow; Brain; Brain Ischemia; C-terminal; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrovascular system; Chronic; Cognitive; Complex; Data; Defect; Development; ENG gene; Endoglin; Endothelial Cells; Endothelium; EphB4 Receptor; Ephrin B Receptor; Functional disorder; Generations; Growth; Human; Impairment; Injury; Intervention; Ischemia; Lesion; Ligands; Link; Mediating; Metabolic; Molecular; Mus; Nerve Degeneration; Neuronal Dysfunction; Neurons; Pathogenesis; Pathologic; Pathway interactions; Peptides; Pharmacologic Substance; Play; Production; Proteins; Proteolytic Processing; Reporting; Role; Signal Transduction; System; Testing; Tissues; Toxic effect; Vascular Diseases; Vascular System; angiogenesis; base; brain endothelial cell; cadherin 5; cerebral microvasculature; density; familial Alzheimer disease; gamma secretase; genome-wide; human disease; in vivo; ischemic lesion; mouse model; mutant; neovascularization; neuroimaging; neuron loss; neuronal survival; neuropathology; neurovascular; novel; protein complex; protein expression; raf-1 Protein; receptor; repaired; response; restoration; tissue repair; vascular abnormality

Cerebral microvasculature abnormalities, such as degeneration of the capillary endothelium, are implicated in the genesis of Alzheimer's disease (AD) neuropathology. In addition, ischemic lesions that cause neuronal damage are often found in AD brains. The brain responds to ischemia by stimulating tissue neovascularization via sprouting angiogenesis; impairment of this function renders the brain vulnerable to the insult. It has been hypothesized that decreased angiogenesis in AD leads to insufficient blood flow and neuronal dysfunction in affected areas. The EphB4/ephrinB2 (efnB2) ligand-receptor system is known to regulate brain angiogenesis in response to ischemia. We present evidence that Presnilin1 (PS1), an important factor in familial AD (FAD), regulates angiogenic functions of EphB4/efnB2 such as stimulation of VE-cadherin angiogenic complexes in brain endothelial cells (ECs). We also found that this function is impaired by PS1 FAD mutants. In addition, we found that ischemia stimulates formation of the same angiogenic complexes in the brain and that this function is attenuated by PS1 FAD mutants together with ischemia-induced neovascularization and cerebral blood flow while neuronal death is increased. We also found that PS1 FAD mutants decrease the γ-secretase processing of efnB2 and production of the angiogenic peptide efnB2/CTF2 thus impairing the response of brain ECs to angiogenic factors. Together, our data support the hypothesis that PS1 FAD mutants inhibit ischemia-induced angiogenic functions of ECs by decreasing the γ-secretase processing of efnB2 and impairing the EphB4/efnB2 signaling, thus decreasing neovascularization in the adult brain and leading to increased vulnerability to this toxic insult and neuronal death. In this application we examine the roles of PS1 FAD mutants and γ-secretase on ischemia-induced angiogenic complexes, blood flow, angiogenesis and neuronal death. In addition, we propose to test a small peptide, which derives from the proteolytic processing of efnB2 by γ-secretase and which we found to rescue angiogenic functions of PS1 FAD ECs, for its pro-angiogenic and neuroprotective functions in brains expressing FAD mutants. In addition we aim to search for novel ischemia-induced angiogenic pathways that are impaired by PS1 FAD mutants and examine whether VE-cadherin angiogenic complexes and angiogenic protein expression are impaired in brains of human PS1 FAD and AD patients.

大脑微血管异常，例如毛细血管内皮变性，与此有关 阿尔茨海默病 (AD) 神经病理学的起源。此外，引起神经元损伤的缺血性病变也常见于AD大脑中。大脑通过发芽血管生成刺激组织新血管形成来应对缺血；该功能的受损使大脑容易受到伤害。据推测，AD 中血管生成减少会导致受影响区域血流不足和神经元功能障碍。已知 EphB4/ephrinB2 (efnB2) 配体受体系统可调节脑血管生成以应对缺血。我们提供的证据表明，Presnilin1 (PS1) 是家族性 AD (FAD) 的重要因素，可调节 EphB4/efnB2 的血管生成功能，例如刺激脑内皮细胞 (EC) 中的 VE-钙粘蛋白血管生成复合物。我们还发现 PS1 FAD 突变体会​​损害该功能。此外，我们发现缺血会刺激大脑中相同血管生成复合物的形成，并且PS1 FAD突变体以及缺血诱导的新血管形成和脑血流会减弱这种功能，同时神经元死亡会增加。我们还发现PS1 FAD突变体减少了efnB2的γ-分泌酶加工和血管生成肽efnB2/CTF2的产生，从而损害了脑EC对血管生成因子的反应。总之，我们的数据支持这样的假设：PS1 FAD 突变体通过减少 efnB2 的 γ-分泌酶处理并损害 EphB4/efnB2 信号传导来抑制缺血诱导的 EC 血管生成功能，从而减少成人大脑中的新血管形成，并导致更容易受到这种毒性损伤和神经元死亡。在此应用中，我们研究了 PS1 FAD 突变体和 γ-分泌酶对缺血诱导的血管生成复合物、血流、血管生成和神经元死亡的作用。此外，我们建议测试一种小肽，该小肽源自 γ-分泌酶对 efnB2 的蛋白水解加工，我们发现它可以挽救 PS1 FAD EC 的血管生成功能，因为它在表达 FAD 突变体的大脑中具有促血管生成和神经保护功能。此外，我们的目标是寻找 PS1 FAD 突变体损害的新的缺血诱导的血管生成途径，并检查 VE-钙粘蛋白血管生成复合物和血管生成蛋白表达是否在人类 PS1 FAD 和 AD 患者的大脑中受损。